Journal
GASTROENTEROLOGY
Volume 128, Issue 1, Pages 74-85Publisher
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2004.10.044
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- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [Z01AI000833, ZIAAI000354, ZIAAI000432, ZIAAI000833, Z01AI000432, Z01AI000354] Funding Source: NIH RePORTER
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Background& Aims: Mice with a disrupted gene for the G-protein alpha inhibitory 2 chain (Gnai2(-/-)) develop a spontaneous colitis resembling human inflammatory bowel disease. Disease expression differs markedly between inbred strains of mice, indicating genetic control of disease susceptibility. We performed a genome-wide screen to localize the chromosomal regions regulating disease expression. Methods: A total of 284 F2 mice derived from resistant C57BL/6J Gnai2(-/-) mice and susceptible C3H/HeN Gnai2(-/-) mice were analyzed in a genome-wide screen for colitis susceptibility and severity. Result : A highly significant locus on chromosome 3 (Gpdc1) contributed to colitis susceptibility and severity (likelihood ratio statistics [LRS] = 32.4; LOD score = 7; P < 1.0 X 10(-5)). The peak linkage of this locus at 62 cM colocalizes exactly with a previously identified locus controlling colitis susceptibility in interleukin-10 -deficient mice. In addition, evidence for linkage with a locus on chromosome 1 (Gpdc2; LIRS = :19.7; LOD = 4.3) was found, and the 2 loci interacted epistatically (combined LIRS = 68.2). A third locus (Gpdc3) was found on chromosome 9 and this locus interacted epistatically with a locus on chromosome 7, which by itself did not have an effect on the trait. Conclusions: The identification of a major locus on chromosome 3 that controls susceptibility to spontaneous colitis in 2 different gene-knockout models indicates that this locus harbors a gene(s) that plays a key role in maintaining mucosal homeostasis. Identification of this gene(s) may contribute to further understanding of the mechanisms underlying human inflammatory bowel disease.
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